Endocrine Abstracts

The adrenal steroid dehydroepiandrosterone (DHEA) is the most prominent circulating steroid in humans and is also a precursor for sex steroids in peripheral tissues. In prostate, DHEA is a substrate for two major metabolic pathways that produce antagonistic sex steroids. In one pathway, DHEA is converted into potent 5alpha-reduced androgens such as 5alpha-dihydrotestoterone (DHT) and thus shares with testicular androgens the control of prostate growth and functions in both normal and cancerous states. In the other, DHEA is metabolised to 7alpha-hydroxyDHEA (7HD) by CYP7B, a novel P450 enzyme originally characterised in mouse brain. Our cyp7b -/- mice have no 7alpha-hydroxylation in brain or in prostate showing that cyp7b is the only enzyme responsible for this reaction in prostate.
We have now examined the 7alpha-hydroxylation in human prostate. NADPH-dependent 7alpha-hydroxylation was confirmed for 3beta-hydroxysteroids including DHEA and androstenediol. This activity was inhibited by clotrimazole, a P450 enzyme blocker. We have found significant levels of 7HD in human prostate samples suggesting that DHEA 7alpha-hydroxylation represents a major metabolic pathway for DHEA in vivo. RNA analysis (reverse-transcription combined with PCR and in situhybridisation) showed high expression of CYP7B mRNA in human benign prostate hyperplasia, in the epithelial cells and also in the prostate vasculature, suggesting that CYP7B catalyses oxysterol 7alpha-hydroxylation within the prostate. Employing human primary prostate cell cultures of fibroblasts and epithelial cells, we have shown that human prostate epithelial cells in culture maintain a high level of 7alpha-hydroxylase activity. Moreover, CYP7B activity in the epithelial cells is enhanced in co-culture of epithelial cells and fibroblasts. In prostate cancer and in immortalised prostate cancer cell lines, CYP7B activity appears to be reduced or absent. For all these reasons, CYP7B may be a key modulator of steroid levels and actions in human prostate.